A series of aromatic disulfide compounds were submitted to the program by Parke-Davis, NSCs 654077D, 670549D, 659881D, 659878D, and received DN2A approval for preclinical development as anti-HIV agents in June, 1994. These compounds were shown by Dr. William G. Rice, SAIC-FCRDC, to be novel inhibitors of HIV nucleocapsid protein zinc fingers. The EC50 values of these compounds in the primary NCI in vitro anti-HIV screen ranged from approximately 0.2-10 microM. Information provided by Parke-Davis indicated that several of these these compounds possess unsuitable pharmaceutical properties: NSC 654077D and NSC 659881D are poorly soluble in vehicles suitable for parenteral administration; NSC 659881D is unstable under physiological conditions. In addition, we found that NSC 654077D and NSC 670549D are rapidly cleared from systemic circulation following bolus i.v. injection to mice (biological half-life < 15 min) and exhibit negligible systemic availability (< 0.5%) when given orally. In contrast, the DL-isoleucine derivative is soluble, stable and bioavailable. Plasma levels provided by a single oral dose of 250 mg/kg, remained within the range of concentrations effective against HIV-1 in vitro for at least 12 hr. Thus, the L-isoleucine disulfide derivative (NSC 672594D) was selected as the principal candidate for preclinical development. The `total drug' plasma pharmacokinetics of NSC 672594D was characterized in male Harlan CD2F1 mice at doses of 50, 100 and 250 mg/kg given by the i.v. and p.o. routes. On the basis of the single dose pharmacokinetic studies in mice, a 250 mg/kg dose given p.o. every 8 hr should provide continuous systemic exposure to potentially effective drug concentrations. This dosing regimen is being evaluated in in vivo efficacy studies employing the hollow fiber model. N-(L-isoleucyl)- benzisothiazolone (NSC 675753D), identified as a degradation product of the L-isoleucine disulfide (NSC 672594) in aqueous solution, possesses physicochemical and pharmacological properties which suggest that it may be a superior candidate for clinical development than the parent disulfide (NSC 672594D).